PD-1/PD-L1抑制剂在晚期非小细胞肺癌中的治疗进展

程序性死亡受体1(programmed death 1,PD-1)抑制剂Pembrolizumab进入一线正式标志着免疫检查点抑制剂在晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗体系中占据了重要地位.临床试验结果证实PD-1/程序性死亡配体1(programmed death ligand 1,PD-L1)抑制剂在晚期NSCLC的一线、二线和多药耐药后治疗的疗效均要优于传统的化疗.一线使用Pembrolizumab联合化疗的客观有效率(objective response rate,ORR)最高可达80%;单药Pembrolizumab的无疾病进展时间(progression-free survival,PFS)接近1年(10.3个月),死亡风险比含铂双药化疗下降40%.单药Pembrolizumab、Nivolumab和Atezolizumab用于二线的疗效同样突出,总生存时间(overall survival,OS)可至1年左右.PD-L1的表达是PD-1/PD-L1抑制剂疗效的预测因子,在晚期NSCLC中阳性(≥1%)的比例约为60%左右,组织类型间差异不大,但是目前并无检测的金标准.     

Targeting the PD-1/PD-L1 axis in non–small cell lung cancer

The last decade has witnessed rapid advances in the discovery and development of immune checkpoint inhibitors in cancer medicine, particularly drugs targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in non–small cell lung cancer (NSCLC). The proven antitumor efficacy coupled with low rates of drug-related toxicities observed, albeit idiosyncratic, with these novel immunotherapeutics have led to the registration of multiple PD-1 and PD-L1 inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, in second-line advanced NSCLC, whereas durvalumab and avelumab are in late-phase clinical testing. Moreover, pembrolizumab has shown a survival advantage in the first-line setting; however, nivolumab failed to show a survival benefit possibly relating to patient selection based on PD-L1 expression. Current patient selection is based on PD-L1 expression, using the relevant companion diagnostic test, where patients with strong PD-L1 expression being more likely to respond to these novel agents. Ongoing clinical research focuses on the development of PD-1 and PD-L1 inhibitor monotherapy in neoadjuvant and adjuvant NSCLC. There is also much interest in using these drugs as a therapeutic backbone for rational combinations with other treatment modalities including cytotoxic chemotherapies in the first-line NSCLC, other immunotherapies such as cytotoxic T-lymphocyte–associated protein 4 antagonists, molecularly targeted agents including EGFR and ALK inhibitors, and radiotherapy. Concurrent treatment with radiotherapy is of particular interest owing to the potential for the abscopal effect, using radiotherapy to facilitate systemic treatment.     

How to make the best use of immunotherapy as first-line treatment of advanced/metastatic non-small-cell lung cancer

Antibodies that target programmed death 1 (PD-1) or its ligand [programmed death ligand 1 (PD-L1)] have become a mainstay of first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC) without targetable genetic alterations. In this review, we summarize results from recent clinical trials that have evaluated the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies atezolizumab and durvalumab as first-line treatment as monotherapy and in combination with chemotherapy, other immunotherapies, and antiangiogenesis agents. We discuss factors that may influence treatment selection, including patient baseline clinical and demographic characteristics, tumor histology, and biomarkers such as PD-L1 expression and tumor mutation burden. While immunotherapy has become a central component of first-line treatment of most patients with advanced NSCLC, important questions remain about how treatment should be managed for individual patients.     

Programmed Death 1 and Programmed Death Ligand 1 Inhibitors in Advanced and Recurrent Urothelial Carcinoma: Meta-analysis of Single-Agent Studies

We performed a systematic review and meta-analysis on the response rates of patients with treatment-refractory urothelial carcinoma treated with programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors. We reviewed the literature for prospective studies evaluating PD-1/PD-L1 inhibitors in refractory urothelial carcinoma patients, which formed the basis for US Food and Drug Administration approval of 5 different antagonistic antibodies targeting PD-1 or PD-L1 (atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab). We considered studies examining PD-1/PD-L1–treated patients, which we identified using the following key terms in the Pubmed, Scopus, Web of Science, ClinicalTrial.gov, and Cochrane Library databases. Eligible studies had ≥ 20 patients each and reported response rates, duration of response, and overall survival (OS). We performed fixed and random-effects meta-analyses to model the point estimates for objective response rate and complete response. The median progression-free survival (PFS) and OS for studies reporting these statistics were evaluated. We found 10 eligible studies that met our inclusion criteria, providing extractable numerators and denominators for response rates, PFS, and OS for 1934 patients with metastatic urothelial carcinoma. The objective response rate was 18% (95% confidence interval, 15-22) for second-line or later therapies. The random-effects estimate for complete response was 4% (95% confidence interval, 3-5), including all disease locations and all PD-1 and PD-L1 inhibitors. Median OS and PFS were < 13 months and 3 months, respectively, across all studies, irrespective of PD-L1 expression. We found that the estimated response rates of agents included in this meta-analysis seem to be more favorable than other salvage therapies.     

Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network Meta-Analysis

IntroductionA series of randomized controlled trials have investigated different first-line immunotherapy combinations, but the optimal combination strategy is yet to be established.MethodsWe performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences. We included published and gray sources of randomized clinical trials comparing immunotherapy combinations with other treatments as first-line treatments for patients with advanced NSCLC. This study was registered in the Prospective Register of Systematic Reviews (CRD42020210501) to ensure transparency.ResultsWe analyzed a total of 16 studies involving 8278 patients and including 10 immunotherapy combinations. For patients without programmed death-ligand 1 (PD-L1) selection, pembrolizumab plus chemotherapy was found to be comparable with sintilimab plus chemotherapy in providing the best overall survival (OS) benefit (hazard ratio = 0.96, 95% confidence interval [CI]: 0.72–1.29). Furthermore, atezolizumab plus bevacizumab plus chemotherapy seemed to provide the best progression-free survival (hazard ratio = 0.45, 95% CI: 0.36–0.55) and the best objective response rate (OR = 0.23, 95% CI: 0.12–0.42). Subgroup analysis by PD-L1 suggested that nivolumab plus ipilimumab plus chemotherapy was associated with the best OS in patients with PD-L1 less than 1% and that pembrolizumab plus chemotherapy was associated with the best OS in patients with PD-L1 greater than or equal to 1%. Pembrolizumab and sintilimab were associated with relatively fewer grade greater than or equal to 3 adverse events when compared with other immunotherapies combined with chemotherapy.ConclusionsOur results suggest that antiprogrammed death-1 combinations are associated with potentially higher survival outcomes than anti–PD-L1 combinations with comparable safety profiles. Moreover, pem-chemo and nivo-ipi-chemo seem to be superior first-line immunotherapy combinations for patients with advanced NSCLC with positive and negative PD-L1 expression, respectively. Although atezo-beva-chemo treatment provided the best progression-free survival and objective response rate, the addition of chemotherapy to immunotherapy would increase the toxicity, especially when antiangiogenesis drugs are simultaneously added.     

Programmed Death-Ligand 1 Tumor Proportion Score and Overall Survival From First-Line Pembrolizumab in Patients With Nonsquamous Versus Squamous NSCLC

IntroductionFor patients with NSCLC receiving immune checkpoint inhibitors, programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) has been validated as a predictive biomarker for improved overall survival (OS). Nevertheless, its histology-specific predictive value in patients with advanced squamous versus nonsquamous cancers remains unclear. To evaluate the differential value of PD-L1 TPS as a predictive biomarker for OS after first-line pembrolizumab in patients with squamous versus nonsquamous NSCLC.MethodsRetrospective, observational study of patients diagnosed with having advanced NSCLC who were treated between October 2015 and April 2019 at community oncology clinics and academic medical centers in a deidentified electronic health record–derived database. Included patients were diagnosed with having advanced or metastatic NSCLC, received treatment with first-line, single-agent pembrolizumab, and had documentation of PD-L1 testing with a numeric result. Exclusion criteria included alterations in EGFR, ALK, and ROS1. The primary end point was OS from start of first-line pembrolizumab therapy by squamous or nonsquamous histology and PD-1 expression level measured by TPS (low, <50% or high, ≥50%).ResultsThe cohort of 1460 patients with NSCLC who received pembrolizumab as a first-line therapy had a mean age of 72 years. Histology was 28% squamous and 72% nonsquamous. PD-L1 expression was low in 13% and high in 87%. No meaningful differences in age, sex, or smoking history were observed by PD-L1 TPS or histology type. A generalized gamma model adjusting for sex and stage at diagnosis found that for patients with nonsquamous histology, high PD-L1 TPS was significantly associated with improved OS by a median OS difference of 8.4 months (p < 0.001). In contrast, for patients with squamous histology, there was no evidence of association between PD-L1 expression level and OS (p = 0.283). PD-L1–related incremental differences in median OS between the patients with squamous and nonsquamous tumors were significantly different (p = 0.034).ConclusionsAmong patients with NSCLC treated with first-line pembrolizumab, high PD-L1 TPS is associated with OS among patients with nonsquamous NSCLC, but not among patients with squamous NSCLC.     

Association of PD-L1 expression status with the efficacy of PD-1/PD-L1 inhibitors and overall survival in solid tumours: A systematic review and meta-analysis

Whether PD-L1-positive patients derive more overall survival benefit from PD-1/PD-L1 inhibitors in the treatment of advanced solid tumours is unclear. We systematically searched the PubMed, Cochrane library and EMBASE databases from January 1, 1966 to March 1, 2019, to identify randomised controlled trials of PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, durvalumab and avelumab) that had available hazard ratios (HRs) for death according to PD-L1 status. A random-effects model was used to calculate the pooled overall survival (OS) HR and 95% CI among PD-L1-positive and PD-L1-negative patients. An interaction test was performed to evaluate the heterogeneity between the two estimates. A total of 24 randomised trials, involving 12,966 participants, fulfilled the inclusion criteria. An OS benefit of PD-1/PD-L1 inhibitors was found in both PD-L1-positive patients (HR, 0.65; 95% CI, 0.60–0.70) and PD-L1-negative patients (HR, 0.82; 95% CI, 0.74–0.91) even at the minimum cut-off value of 1%. Significant differences in the efficacy of PD-1/PD-L1 inhibitors between PD-L1-positive and PD-L1-negative patients were noted at different cut-off values. Moreover, there was a positive dose–response relationship between PD-L1 positivity and OS benefit (HR for 1%, 0.58, [0.50, 0.67]; 5%, 0.52 [0.43, 0.64]; 10%, 0.50 [0.40, 0.63]). Subgroup analyses showed that these results were generally consistent, regardless of study design, line of treatment, treatment type, tumour type, PD-L1 staining cell type and median follow-up time. We demonstrated that PD-1/PD-L1 inhibitors significantly improved OS in both PD-L1 positive and PD-L1 negative patients compared to controls, but the magnitude of benefit was clinically PD-L1-dependent.     

A Multicenter,Randomized Phase III Study Comparing Platinum Combination Chemotherapy Plus Pembrolizumab With Platinum Combination Chemotherapy Plus Nivolumab and Ipilimumab for Treatment-Naive Advanced Non–Small Cell Lung Cancer Without Driver Gene Alterations: JCOG2007 (NIPPON Study)

BackgroundFirst-line treatment of non–small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor, regardless of the expression level of the programmed cell death–1 (PD-1) ligand PD-L1 on tumor cells. Moreover, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte–associated protein–4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. We have now designed a randomized, controlled phase III trial (NIPPON, JCOG2007) to confirm that platinum combination chemotherapy plus nivolumab and ipilimumab is superior to such chemotherapy plus pembrolizumab (antibody to PD-1) for treatment-naive patients with advanced NSCLC.Patients and MethodsChemotherapy-naïve patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive platinum combination chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. Patients with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Enrollment of 422 patients over 3 years at 55 oncology facilities throughout Japan is planned. The primary endpoint is overall survival. In addition, as ancillary research, metagenomic analysis of the gut microbiota will be performed with fecal samples collected before treatment onset, and the results will be examined for their association to therapeutic effect and adverse events.ConclusionIf the primary endpoint is met, platinum combination chemotherapy together with nivolumab plus ipilimumab will be established as a new, more effective standard treatment for advanced NSCLC.     

Clinical outcomes and influencing factors of PD-1/PD-L1 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has an increasing incidence worldwide, and the global 5-year survival rate ranges from 5–30%. In China, HCC seriously threatens the nation''s health; the incidence of HCC ranks fourth among all theriomas, and the mortality rate is the third highest worldwide. The main therapies for HCC are surgical treatment or liver transplantation; however, most patients with HCC will experience postoperative recurrence or metastasis, eventually resulting in mortality. As for advanced or unresectable HCC, the current appropriate treatment strategy is transarterial chemoembolization; however, limited therapeutic effect and natural or acquired drug resistance affect the efficacy of this approach. Previous studies have demonstrated that PD-L1 expression on host cells and myeloid cells plays an important role in PD-L1 blocked-mediated tumor regression. Thus, further research on programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) is required. Countries including the United States, France, Britain and China have developed PD-1/PD-L1 blockers, including nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, toripalimab, sintilimab and camrelizumab. Notably, all of these blockers have therapeutic effect and influencing factors in HCC. Factors that influence the clinical outcome of PD-1 have also been discovered, such as inflammatory genes, specific receptors and signaling pathways. The discovery of these factors will help to identify novel methods, such as combination treatment, to decrease the influence of other factors on the efficacy of PD-1/PD-L1. Sorafenib and lenvatinib have been approved for first-line treatment for patients with advanced HCC. When first-line treatment frequently fails, pembrolizumab and ipilimumab plus nivolumab are used following sorafenib (but not lenvatinib) treatment in advanced HCC. Thus, tumor immunotherapy using PD-1/PD-L1 blockers exhibits promising outcomes for the treatment of HCC, and more novel PD-1/PD-L1 inhibitors are being developed to fight against this disease. The present review discusses the clinical results and influencing factors of PD-1/PD-L1 inhibitors in HCC to provide insight into the development and optimization of PD-1/PD-L1 inhibitors in the treatment of HCC.     

Five Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel for Previously Treated,Programmed Death-Ligand 1–Positive Advanced NSCLC

IntroductionIn the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study.MethodsPatients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m² once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis.ResultsA total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0‒77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44‒0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61‒0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (∼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab.ConclusionsPembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting.     

Immune Checkpoint Inhibitors for Patients With Advanced Non–Small-Cell Lung Cancer: A Systematic Review

Second-line treatment options are limited for patients with advanced non–small-cell lung cancer (NSCLC). Standard therapy includes the cytotoxic agents docetaxel and pemetrexed, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib. Immune checkpoint inhibitors are a new class of treatment that have shown durable overall radiologic response rates and have been well tolerated. The objective of this systematic review was to investigate the efficacy of immune checkpoint inhibitors compared with other chemotherapies in patients with advanced NSCLC. Medline, Embase, and PubMed were searched for randomized controlled trials comparing treatment with immune checkpoint inhibitors against treatment with chemotherapy in patients with stage IIIB or IV NSCLC. Nine randomized controlled trials with 15 publications were included. A significant overall survival benefit of second-line nivolumab (nonsquamous: hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.60-0.77; P < .001; squamous: HR = 0.59, 95% CI, 0.44-0.79; P < .001) or second-line atezolizumab (HR = 0.73, 95% CI, 0.62-0.87; P = .0003) or second-line pembrolizumab (in patients with programmed cell death ligand 1 [PD-L1]-positive tumors) (pembrolizumab 2 mg/kg HR = 0.71, 95% CI, 0.58-0.88; P = .0008; pembrolizumab 10 mg/kg HR = 0.61, 95% CI, 0.49-0.75; P < .0001) or first-line pembrolizumab (HR = 0.60, 95% CI, 0.41-0.89; P = .005) compared with chemotherapy was found. The adverse effects were mainly higher in the chemotherapy arms. For patients with advanced stage IIIB/IV NSCLC, the improvement in overall survival outweighed the harms and supported the use of first-line pembrolizumab (in patients with ≥ 50% PD-L1–positive tumors) or second-line nivolumab, atezolizumab, or pembrolizumab (in patients with PD-L1–positive tumors).     

Immunotherapy in Squamous Cell Cancer of the Esophagus

Treatment of esophageal carcinoma has changed dramatically following several landmark trials, which have proven the benefit of immunotherapy. The selective PD-1 (programmed cell death ligand-1)-inhibitor nivolumab has been shown to improve DFS in the adjuvant therapy setting (CheckMate-577). In the first-line treatment, PD-L1 positive (CPS ≥ 10) squamous cell carcinoma patients (pts) have been shown to have an increased OS following treatment with the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). Nivolumab also improved overall survival in the first line setting either combined with ipilimumab or with chemotherapy (CheckMate 648) compared to chemotherapy alone. In Asian first-line patients, phase III trials investigating camrelizumab (ESCORT 1), toripalimab (JUPITER 06), or sintilimab (ORIENT 15) in addition to chemotherapy also showed significant survival benefits. In the second-line setting, monotherapy with nivolumab (ATTRACTION-03), pembrolizumab (KEYNOTE-181), camrelizumab (ESCORT), and tislelizumab (RATIONALE 302) demonstrated a benefit in OS in comparison to chemotherapy. Here we will review these trials and integrate them into the current treatment algorithm.     

Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1–Selected NSCLC

IntroductionIMpower110 previously revealed significant overall survival (OS) benefit with atezolizumab versus chemotherapy in patients with treatment-naive EGFR- and ALK-negative (wild type [WT]) metastatic NSCLC with high programmed death-ligand 1 (PD-L1) expression (≥50% on tumor cells [TCs] or ≥10% on tumor-infiltrating immune cells [ICs], per SP142 immunohistochemistry assay; p = 0.0106). We present primary OS analyses in lower PD-L1 expression groups and an updated, exploratory analysis in the high PD-L1 expression group.MethodsThis open-label, phase 3 trial randomized patients with PD-L1 expression on greater than or equal to 1% of TC or IC to receive atezolizumab or platinum-based chemotherapy. The primary end point was OS, hierarchically tested in PD-L1 expression WT subgroups: first the high PD-L1 expression subgroup, then the high-or-intermediate PD-L1 expression subgroup (≥5% on TC or IC), and then the any PD-L1 expression subgroup (≥1% on TC or IC).ResultsThe any PD-L1 expression WT population included 554 patients (excluded 18 EGFR- or ALK-positive patients). With 17 months’ additional follow-up, OS improvement in the atezolizumab versus chemotherapy arm was not statistically significant in high-or-intermediate PD-L1 expression WT patients (n = 328; hazard ratio = 0.87, 95% confidence interval: 0.66–1.14, p = 0.3091; median = 19.9 versus 16.1 mo), precluding formal OS testing in any PD-L1 expression WT patients. Exploratory analysis in high PD-L1 expression WT patients (n = 205) revealed maintained OS benefit in the atezolizumab arm (hazard ratio = 0.76, 95% confidence interval: 0.54–1.09; median = 20.2 versus 14.7 mo). Updated safety data continued to favor atezolizumab.ConclusionsStatistical significance for OS was not revealed in the high-or-intermediate expression WT group, and, as a result, OS in the any PD-L1 expression WT group was not formally tested. No new safety signals were found. This updated analysis of IMpower110 supports using atezolizumab in treatment-naive, metastatic WT NSCLC with high PD-L1 expression.     

PD-1抑制剂治疗复发难治性胸腺瘤1例报道及文献复习

目的:探讨程序性细胞死亡蛋白1及其配体（PD-1/PD-L1）抑制剂在胸腺瘤治疗中的应用。方法:回顾性分析四川大学华西医院收治的1例晚期胸腺瘤患者使用PD-1抑制剂pembrolizumab的临床资料并对相关文献进行回顾。以“PD-1 inhibitor”、“PD-L1 inhibitor”、“pembrolizumab”、“nivolumab”或“atezolizumab”联合“thymoma”检索Pubmed数据库,检索时间截止至2019年9月30日。结果:患者男,26岁,B2/B3型胸腺瘤,在多次姑息性手术治疗,多线化疗,纵隔放疗后病情出现进展,后续使用PD-L1抑制剂pembrolizumab联合培美曲塞治疗,在第一次使用pembrolizumab治疗后患者出现免疫相关心肌炎,经甲基强的松龙治疗后好转,药物减停过程中患者出现心肌炎复燃,并伴随全身多器官功能障碍,最后在使用PD-1抑制剂后5个月死亡。在Pubmed数据库共检索到5篇文献共12例胸腺瘤患者使用免疫治疗,加上本例共13例。在这13例使用PD-1抑制剂的患者中,9例进行了疗效评价,3例患者达到部分缓解,6例患者疾病稳定;然而有11例患者出现免疫相关不良事件,6例患者死亡。结论:PD-1抑制剂在胸腺瘤中显示出良好的抗肿瘤活性,同时也具有很高的不良反应发生率及致死率,在临床应用中应慎重考虑患者的获益和风险。     

Looking for the best immune‐checkpoint inhibitor in pre‐treated NSCLC patients: An indirect comparison between nivolumab,pembrolizumab and atezolizumab

Immune‐checkpoint inhibitors represent the new standard of care in patients with advanced NSCLC who progressed after first‐line treatment. This work aim to assess any difference in both efficacy and safety profiles among Nivolumab, Pembrolizumab and Atezolizumab in pre‐treated NSCLC patients. Randomized clinical trials comparing immune‐checkpoint inhibitor versus docetaxel in pre‐treated patients with advanced NSCLC were included and direct comparison meta‐analysis of selected trials have been performed. Subsequently the summary estimates of Nivolumab, Pembrolizumab and Atezolizumab emerging from the direct meta‐analysis were selected to provide the pooled estimates of hazard ratio (HR) and relative risk (RR) for the indirect comparisons among these agents. A total of 5 studies met the selection criteria and were included in the meta‐analysis. Indirect comparisons for efficacy outcomes showed the RR for ORR nivolumab versus atezolizumab 1.66 (95% CI 1.07?2.58), pembrolizumab versus atezolizumab 1.94 (95% CI 1.30?2.90). No significant differences in both PFS and OS have been observed. Indirect comparisons for safety showed the RR for G3‐5 AEs nivolumab versus pembrolizumab 0.41 (95% CI 0.29?0.60), nivolumab versus atezolizumab 0.50 (95% CI 0.35?0.72). No significant differences in both pneumonitis and discontinuation rate have been observed. The results of this work revealed that nivolumab and pembrolizumab are associated with a significant increase of ORR as compared to atezolizumab and nivolumab is associated with a significant lower incidence of G3‐5 AEs as compared to the other drugs. These evidences could support the oncologists to select the best drug for each patient.     

PD-1/PD-L1抑制剂在晚期肝细胞肝癌治疗中的研究进展

晚期原发性肝细胞肝癌(hepatocellular carcinoma,HCC)的系统治疗主要包括靶向治疗、化疗以及免疫治疗。近3年,程序性死亡受体-1(programmed death receptor-1,PD-1)/程序性死亡受体-1配体(programmed death receptor-1 ligand,PD-L1)抑制剂在晚期HCC治疗中取得突破性进展。纳武单抗(nivolumab)和帕博利珠单抗(pembrolizumab)先后被美国食品药品管理局(FDA)批准用于HCC二线治疗。多个PD-1/PD-L1抑制剂联合系统治疗的Ⅰ、Ⅱ期临床研究初步显示出较好的疗效和安全性。阿特珠单抗(atezolizumab)联合贝伐单抗一线治疗成为首个在Ⅲ期临床研究中证实优于现有标准治疗索拉非尼的全新疗法。本文就近年PD-1/PD-L1抑制剂在晚期HCC治疗中的研究进展进行概述。     

Prognostic Impact and Risk Factors of Immune-Related Pneumonitis in Patients With Non–Small-Cell Lung Cancer Who Received Programmed Death 1 Inhibitors

IntroductionPneumonitis is one of the immune-related adverse events of programmed death 1 (PD-1) inhibitors that sometimes cause lethal outcomes. Although some recent reports have described PD-1 inhibitors as more effective in non–small-cell lung cancer (NSCLC) patients with immune-related adverse events than in those without, few data are available on the prognosis of those treated with PD-1 inhibitors who developed immune-related pneumonitis (IRP). Additionally, the robust risk factors of IRP have not been well elucidated.Patients and MethodsA retrospective review of patients with recurrent or advanced NSCLC who took a PD-1 inhibitor (nivolumab or pembrolizumab monotherapy) between January 2016 and March 2018 was undertaken. Radiologic findings such as unilateral infiltration were also defined as IRP as long as they were deemed relevant to PD-1 inhibitors.ResultsTwenty-seven (16%) of 170 patients developed IRP. Although 22 (81%) of 27 patients with IRP recovered with drug cessation with or without corticosteroid therapy, 8-week landmark analysis showed the overall survival after administration of the PD-1 inhibitor was significantly shorter in patients with IRP than in those without (8.7 vs. 23.0 months, P = .015). Patients with IRP tended to not receive next-line treatment and choose best supportive care after cessation of PD-1 inhibitor therapy. In the multivariate analysis, pembrolizumab (vs. nivolumab) and low serum albumin were independent risk factors for IRP.ConclusionDevelopment of IRP was correlated with poor prognosis in patients with NSCLC. Further study is necessary for establishing the best prediction and management strategies for IRP.     

Three-Year Follow-Up of Neoadjuvant Programmed Cell Death Protein-1 Inhibitor (Sintilimab) in NSCLC

IntroductionProgrammed cell death protein-1 (PD-1) inhibitors have been proved to be feasible and to have efficacy in multiple cancers, including NSCLC. But few studies have evaluated the effectiveness of PD-1 inhibitor as neoadjuvant therapy with a long-term follow-up. Here, in this phase 1b study with a 3-year follow-up, we reported the clinical outcomes of patients who received the PD-1 inhibitor as neoadjuvant therapy.MethodsTwo doses of sintilimab (intravenously, 200 mg) were used for patients with stages IA to IIIB NSCLC (registration number: ChiCTR-OIC-17013726). Then, surgery was performed within 29 to 43 days after the first dose. All patients underwent positron emission tomography–computed tomography at enrolment and before surgery to evaluate tumor metabolism after administration of PD-1 inhibitor. We also evaluated the expression of programmed death-ligand 1 (PD-L1) as an exploratory analysis in 32 eligible patients. Safety was the primary end point. Overall survival (OS), disease-free survival (DFS), event-free survival, and major pathologic response were the key secondary end points.ResultsWith the mean follow-up of 37.8 months, 3-year OS rate was 88.5% and the 3-year DFS rate was 75.0% among patients who underwent R0 resection. In patients with positive PD-L1 expression, 3-year OS and DFS rates were 95.5% and 81.8%, respectively. Eight patients had recurrent tumors, including local recurrence, lung metastasis, brain metastasis, and bone metastasis. Patients with PD-L1 greater than or equal to 1% had more favorable clinical outcomes than the other subgroup (hazard ratio = 0.275, 95% confidence interval: 0.078–0.976). No more new adverse events have occurred in the 3-year follow-up because we first reported them in the former publication.ConclusionsThis is the first study to report the long-term survival probability of patients with NSCLC receiving PD-1 inhibitors as the neoadjuvant treatment. The 3-year follow-up results revealed that patients with positive PD-L1 expression and high tumor mutation burden have favorable clinical outcomes.     

KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated,PD-L1-positive,advanced NSCLC

KEYNOTE-033 (NCT02864394) was a multicountry, open-label, phase 3 study that compared pembrolizumab vs docetaxel in previously treated, programmed death-ligand 1 (PD-L1)-positive, advanced non-small cell lung cancer (NSCLC), with most patients enrolled in mainland China. Eligible patients were randomized (1:1) to pembrolizumab 2 mg/kg or docetaxel 75 mg/m² every 3 weeks. Primary endpoints were overall survival (OS) and progression-free survival and were evaluated sequentially using stratified log-rank tests, first in patients with PD-L1 tumor proportion score (TPS) ≥50% and then in patients with PD-L1 TPS ≥1% (significance threshold: P < .025, one-sided). A total of 425 patients were randomized to pembrolizumab (N = 213) or docetaxel (N = 212) between 8 September 2016 and 17 October 2018. In patients with a PD-L1 TPS ≥50% (n = 227), median OS was 12.3 months with pembrolizumab and 10.9 months with docetaxel; the hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.61-1.14; P = .1276). Because the significance threshold was not met, sequential testing of OS and PFS was ceased. In patients with a PD-L1 TPS ≥1%, the HR for OS for pembrolizumab vs docetaxel was 0.75 (95% CI: 0.60-0.95). In patients from mainland China (n = 311) with a PD-L1 TPS ≥1%, HR for OS was 0.68 (95% CI: 0.51-0.89). Incidence of grade 3 to 5 treatment-related AEs was 11.3% with pembrolizumab vs 47.5% with docetaxel. In summary, pembrolizumab improved OS vs docetaxel in previously treated, PD-L1-positive NSCLC without unexpected safety signals; although the statistical significance threshold was not reached, the numerical improvement is consistent with that previously observed for pembrolizumab in previously treated, advanced NSCLC.